Selective inhibition of PKR improves vascular inflammation and remodelling in high fructose treated primary vascular smooth muscle cells

Kalra, Jaspreet; Mangali, Sureshbabu; Bhat, Audesh; Jadhav, Kirtikumar B.; Dhar, Animesh

doi:10.1016/j.bbadis.2019.165606

Cited by 12 publications

(13 citation statements)

References 55 publications

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“…To better understand the function of ERS in PHEV replication, we pretreated N2a cells with 4-phenylbutyric acid (4-PBA), a chemical chaperone that has been reported to reduce ERS by restricting eIF2α phosphorylation ( 42 , 43 ). In PHEV-infected N2a cells, 4-PBA pretreatment lowered eIF2α phosphorylation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…9C ). To verify the role of PKR in eIF2α phosphorylation and PHEV replication, C16, a specific inhibitor of PKR, was utilized to disrupt the PKR signaling pathway ( 43 ). PKR inhibition was confirmed by Western blotting for p-PKR and p-eIF2α ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To further validate that the reduced nascent protein synthesis following PHEV infection was involved in PERK/PKR-triggered eIF2α phosphorylation, GSK2606414 (a PERK-specific inhibitor) and C16 (a PKR-specific inhibitor) were used to investigate protein translation ( 43 ). The addition of GSK2606414 and C16 alone or in combination rescued the global protein translation attenuation of PHEV infection ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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The PERK/PKR-eIF2α Pathway Negatively Regulates Porcine Hemagglutinating Encephalomyelitis Virus Replication by Attenuating Global Protein Translation and Facilitating Stress Granule Formation

Shi

et al. 2022

J Virol

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The replication of coronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is closely associated with the endoplasmic reticulum (ER) of infected cells. The unfolded protein response (UPR), which is mediated by ER stress (ERS), is a typical outcome in coronavirus-infected cells and is closely associated with the characteristics of coronaviruses. However, the interaction between virus-induced ERS and coronavirus replication is poorly understood. Here, we demonstrated that infection with the betacoronavirus porcine hemagglutinating encephalomyelitis virus (PHEV) induced ERS and triggered all three branches of the UPR signaling pathway both in vitro and in vivo. In addition, ERS suppressed PHEV replication in mouse neuro-2a (N2a) cells primarily by activating the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) axis of the UPR. Moreover, another eIF2α phosphorylation kinase, IFN-induced double-stranded RNA-dependent protein kinase (PKR), was also activated and acted cooperatively with PERK to decrease PHEV replication. Furthermore, we demonstrated that the PERK/PKR-eIF2α pathways negatively regulated PHEV replication by attenuating global protein translation. Phosphorylated eIF2α also promoted the formation of stress granule (SG), which in turn repressed PHEV replication. In summary, our study presents a vital aspect of the host innate response to invading pathogens and reveals attractive host targets (e.g., PERK, PKR and eIF2α) for antiviral drugs. IMPORTANCE Coronavirus diseases are caused by different coronaviruses of importance in humans and animals, and specific treatments are extremely limited. ERS, which can activate the UPR to modulate viral replication and the host innate response, is a frequent occurrence in coronavirus-infected cells. PHEV, a neurotropic β-coronavirus, causes nerve cell damage, which accounts for the high mortality rates in suckling piglets. However, it remains incompletely understood whether the highly developed ER in nerve cells plays an antiviral role in ERS and how ERS regulates viral proliferation. In this study, we found that PHEV infection induced ERS and activated the UPR both in vitro and in vivo and that the activated PERK/PKR-eIF2α axis inhibited PHEV replication through attenuating global protein translation and promoting SG formation. A better understanding of coronavirus-induced ERS and UPR activation may reveal the pathogenic mechanism of coronavirus and facilitate the development of new treatment strategies for these diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The PERK/PKR-eIF2α Pathway Negatively Regulates Porcine Hemagglutinating Encephalomyelitis Virus Replication by Attenuating Global Protein Translation and Facilitating Stress Granule Formation

Shi

et al. 2022

J Virol

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“…In fact, vascular smooth muscle cells (VSMCs) from the thoracic aorta of rats treated with high glucose, a well-known source for vascular dysfunction, showed increased PKR expression, accompanied by increased gene-level markers of inflammation, oxidative stress, and apoptosis. Incubation with selective PKR inhibitor, imoxin (C16), attenuated all these effects elicited by high glucose [ 16 ]. Moreover, increased PKR expression followed by vascular impairment and augmented inflammatory markers is observed in an experimental model of hypertension induced by L-NAME treatment [ 17 ].…”

Section: Figmentioning

confidence: 99%

COVID-19 and hypertension: Is there a role for dsRNA and activation of Toll-like receptor 3?

Justina

Giachini

Priviero

et al. 2021

Vascular Pharmacology

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“…However, no studies have been done so far to explore the role of PKR in hypertension related renal damage. Previously, we have reported the association of PKR in endothelial dysfunction, cardiovascular remodeling and renal inflammation [ 18 , 19 ]. In continuation with our previous study, we establish the role of PKR in NG-Nitro-L-arginine Methyl Ester, Hydrochloride (L-NAME) induced renal damage.…”

Section: Introductionmentioning

confidence: 99%

Up-regulation of PKR pathway contributes to L-NAME induced hypertension and renal damage

Kalra

Bhat

Jadhav

et al. 2020

Heliyon

Self Cite

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Hypertension induced kidney damage is often associated with fibrosis and tubular apoptosis. Doublestranded protein kinase (PKR) is a well recognized inducer of inflammation and apoptosis. However, role of PKR in hypertension coupled renal damage is still not explored. Therefore here we sought to investigate the role of PKR in the pathogenesis of L-NAME induced hypertension and renal damage in Wistar rats and the underneath molecular mechanism. Methods: L-NAME (40 mg/kg, p.o) and imoxin (0.5 mg/kg, i.p) was given to Wistar rats for 4 weeks. Increased eNOS expression, serum creatinine, BUN and changes in mean arterial pressure confirmed for hypertensive renal damage. Western blot and immunohistochemistry was carried out for PKR and markers for fibrosis and apoptosis. Morphological alterations were assessed by H&E staining. Sirius red and Masson's Trichrome staining was performed for collagen and fibrosis. TUNEL assay was done for tubular cell death and apoptosis. Results: Increased expression of PKR and its downstream markers were reported in L-NAME rats, attenuation was observed with imoxin treatment. L-NAME treated rats showed a significant increase in MAP, serum calcium, creatinine and BUN along with the significant morphological changes, attenuation was reported with the imoxin treatment. Conclusion: PKR is a core contributor in the pathogenesis of L-NAME induced renal damage and tubular apoptosis. Therapeutically targeting of PKR could be an attractive approach to treat the renal complications associated with hypertension.

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Selective inhibition of PKR improves vascular inflammation and remodelling in high fructose treated primary vascular smooth muscle cells

Cited by 12 publications

References 55 publications

The PERK/PKR-eIF2α Pathway Negatively Regulates Porcine Hemagglutinating Encephalomyelitis Virus Replication by Attenuating Global Protein Translation and Facilitating Stress Granule Formation

The PERK/PKR-eIF2α Pathway Negatively Regulates Porcine Hemagglutinating Encephalomyelitis Virus Replication by Attenuating Global Protein Translation and Facilitating Stress Granule Formation

COVID-19 and hypertension: Is there a role for dsRNA and activation of Toll-like receptor 3?

Up-regulation of PKR pathway contributes to L-NAME induced hypertension and renal damage

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